h-89 and Alzheimer-Disease

The biological cascade of second messenger-cyclic adenosine monophosphate (cAMP) -as a molecular mechanism implicated in memory and learning regulation has captured the attention of neuroscientists worldwide. cAMP triggers its foremost effector, protein kinase A (PKA), resulting in the activation of innumerable downstream targets. Roflumilast (ROF), a phosphodiesterase 4 inhibitor, has demonstrated a greater efficiency in enhancing cAMP signaling in various neurological disorders. This study was conducted to identify various downstream targets of PKA as mechanistic tools through which ROF could hinder the progressive cognitive impairment following central streptozotocin (STZ) administration in mice. Animals were injected with STZ (3 mg/kg/i.c.v) once. Five hours later, mice received ROF (0.4 mg/kg) with or without the PKA inhibitor, H89, for 21 days. ROF highly preserved the structure of hippocampal neurons. It improved the ability of mice to develop short-term memories and retrieve spatial memories in Y-maze and Morris water maze tests, respectively. ROF enhanced the gene expression of ABCB1 transporters and pregnane X receptors (PXR), and hampered Aβ accumulation in hippocampus. Simultaneously, it interfered with the processes of tau phosphorylation and nitration. This effect was associated with an upsurge in hippocampal arginase activity as well as a decline in glycogen synthase kinase-3β activity, nitric oxide synthase (NOS) activity, and inducible NOS expression. Contrariwise, ROF's beneficial effects were utterly abolished by co-administration of H89. In conclusion, boosting PKA, by ROF, modulated PXR/ABCB1 expression and arginase/NOS activities to restrict the main post-translational modifications of tau, Aβ deposition and, accordingly, cognitive deterioration of sporadic Alzheimer's disease.

Topics: Alzheimer Disease; Aminopyridines; Amyloid beta-Peptides; Animals; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzamides; Cognitive Dysfunction; Cyclopropanes; Disease Models, Animal; Hippocampus; Isoquinolines; Male; Mice; Nitric Oxide; Phosphodiesterase 4 Inhibitors; Protein Kinase Inhibitors; Streptozocin; Sulfonamides; Tauopathies

Type 2 diabetes (T2D) may play a relevant role in the development of Alzheimer's disease (AD), however, the underlying mechanism was not clear yet. We developed an animal model presenting both AD and T2D, morris water maze (MWM) test and recognition task were performed to trace the cognitive function. Fasting plasma glucose (FPG) and oral glucose tolerance test (OGTT) were determined to trace the metabolism evolution. TUNEL assay and apoptosis-related protein levels were analyzed for the detection of neuronal apoptosis. Cyclic adenosine monophosphate (cAMP) agonist bucladesine or protein kinase (PKA) inhibitor H-89 were used to determine the effects of cAMP/PKA signaling pathway on IDE expression and neuronal apoptosis. The results showed that T2D contributes to the AD progress by accelerating and worsening spatial memory and recognition dysfunctions. Metabolic parameters and glucose tolerance were significantly changed in the presence of the AD and T2D. The significantly induced neuronal apoptosis and increased pro-apoptotic proteins in mice with AD and T2D were also observed. We showed the decreased expression level of IDE and the activating of cAMP/PKA signaling pathway in AD and T2D mice. Further studies indicated that cAMP agonist decreased the expression level of IDE and induced the neuronal apoptosis in mice with AD and T2D; whereas PKA inhibitor H-89 treatment showed the completely opposite results. Our study indicated that, in the T2D and AD mice, cAMP/PKA signaling pathway and IDE may participate in the contribute role of T2D in accelerating the pathological process of AD via causing the accumulation of Aβ and neuronal apoptosis.

Topics: Alzheimer Disease; Animals; Apoptosis; Blood Glucose; Bucladesine; Cells, Cultured; Cyclic AMP; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucose Tolerance Test; Humans; Insulysin; Isoquinolines; Mice; Neurons; Protein Kinases; Signal Transduction; Sulfonamides